Use of Sharpless asymmetric

Fig. 8. Use of Sharpless asymmetric epoxidation for the preparation of an intermediate in the synthesis of FK-506 (105), where represents the chiral...

Scheme 3. The ARCO Chemical Company s commercial synthesis of the glycidols using the Sharpless asymmetric epoxidatlon reaction.

The development of Sharpless asymmetric epoxidation (SAE) of allylic alcohols in 1980 constitutes a breakthrough in asymmetric synthesis, and to date this method remains the most widely applied asymmetric epoxidation technique [34, 44]. A wide range of substrates can be used in the reaction ( ) -allylic alcohols generally give high enantioselectivity, whereas the reaction is more substrate-dependent with (Z)-allylic alcohols [34]. 

One of the earliest and most important discoveries in metal-catalyzed asymmetric synthesis is Sharpless s Ti-catalyzed epoxidation of allylic alcohols. A mere mention of all the total syntheses that have used this technology would require a separate review article Here, we select Trost s masterful total synthesis of solamin (100, Scheme 14), for its beautiful and multiple use of Sharpless s asymmetric epoxidation.1161 Optically pure epoxy alcohol 95 is converted to both epoxy iodide 96 and diol 97 The latter two intermediates are then united to give 98, which is oxidized and converted to dihydrofuran 99 by a Ramberg-Backlund transformation. The Re catalyzed butenolide annulation that is used to afford the requisite unsaturated lactone only adds to the efficiency of this beautiful total synthesis. 

The paramount importance of Sharpless "asymmetric epoxidation" lies on the fact that the epoxide group is almost as versatile as the carbonyl group (in Heading 5.2 we have referred to it as a "homocarbonyl" group). The method is of general applicability and is relatively indifferent to pre-existing chiral centres, so it may be used iteratively. Moreover, either of the two enantiomers may be obtained, usually... 

Scheme 8 summarizes the introduction of the missing carbon atoms and the diastereoselective epoxidation of the C /C double bond using a Sharpless asymmetric epoxidation (SAE) of the allylic alcohol 64. The primary alcohol 62 was converted into the aldehyde 63 which served as the starting material for a Horner-Wadsworth-Emmons (HWE) reaction to afford an E-configured tri-substituted double bond. The next steps introduced the sulfone moiety via a Mukaiyama redox condensation and a subsequent sulfide to sulfone oxidation. The sequence toward the allylic alcohol 64 was com-... 

An intramolecular diastereoselective Refor-matsky-type aldol approach was demonstrated by Taylor et al. [47] with an Sm(II)-mediated cy-clization of the chiral bromoacetate 60, resulting in lactone 61, also an intermediate in the synthesis of Schinzer s building block 7. The alcohol oxidation state at C5 in 61 avoided retro-reaction and at the same time was used for induction, with the absolute stereochemistry originating from enzymatic resolution (Scheme II). Direct re.solution of racemic C3 alcohol was also tried with an esterase adapted by directed evolution [48]. In other, somewhat more lengthy routes to CI-C6 building blocks, Shibasaki et al. used a catalytic asymmetric aldol reaction with heterobimetallic asymmetric catalysts [49], and Kalesse et al. used a Sharpless asymmetric epoxidation [50]. 

Asymmetric dihydroxylation Sharpless developed a catalytic system (AD-mix- 3 or AD-mix-a) that incorporates a chiral ligand into the oxidizing mixture which can be used for the asymmetric dihydroxylation of alkenes. The chiral ligands used in Sharpless asymmetric dihydroxylation are quinoline alkaloids, usually dihydroquinidine (DHQD) or dihydroquinine (DHQ) linked by a variety of heterocyclic rings such as 1,4-phthalhydrazine (PHAL) or pyridazine (PYR) (see section 1.6, reference 32 of Chapter 1). 

Aminohydroxylation of unsymmetrically substituted alkenes, in contrast to dihydroxylation, may give two possible regioisomers of aminoalcohol derivatives but asymmetric aminohydroxylation, by using the same catalytic system as that used for Sharpless asymmetric dihydroxylation, can be highly regioselective as well as enantioselective. 

Starting from (+)-diethyl tartrate (2), bromobutenolide 18 was obtained in nine steps. Three of the four C=C double bonds were built up using a Wittig reaction (11—>12), an Ando- y Q Horner-Wadsworth-Emmons reaction (13— 15) and (3-elimination (16 18). From (-)-actinol (3) stannane 23 and sulfone 24 were synthesized in 9 and 13 steps, respectively. Their common intermediate, alkyne 22, was synthesized using methoxycarbonylation. Sharpless asymmetric epoxidation and Ci-elongation with lithio trimethylsilyldiazomethane. Stannane 23 was obtained upon hydrostannylation and TBS deprotection. Sulfone 24 was obtained after addition to methyl tetrolate, reduction, Mukaiyama redox condensation, acetylation and catalytic oxidation. 

A total synthesis of LTB has been reported by Corey et al. as outlined in Scheme 3.16. By using the Sharpless asymmetric oxidation, the enantiomer of the epoxy alcohol in Scheme 3.11 was obtained, from which the corresponding aldehyde was then prepared. The epoxy olefin was transformed to the desired Wittig salt 39, which was condensed with the homologated aldehyde 40, giving a modest yield of the desired (8Z)-isomer. Again, the benzoyloxy aldehyde... 

Although the use of yeasts as biocatalysts was quite effective in preparing extremely pure enantiomers of JHs, their synthetic routes were lengthy. Indeed, in the case of (+)-JH I (61), its overall yield was only 0.34% (21 steps) by the biocatalytic method.28 We therefore examined the application of Sharpless asymmetric dihydroxylation for the synthesis of (+)-JH I and (+)-JH II. 

Among the published [114] [116] syntheses of 101, Keinan s synthesis, [116c] making use of Sharpless s asymmetric dihydroxylation, is straightforward and efficient and merits special consideration. Kobayashi s approach [116c] should be mentioned here, too. 

For allylic alcohols, use the Sharpless asymmetric epoxidation reaction. Reagents are t-BuOOH, Ti(Oi-Pr)4 and (-l-)-diethyl (or di-isopropyl) tartrate. Note that the (-1-)-enantiomer of the ligand is required for the formation of the epoxide 6 (place the alcohol in the lower right using the model given in Scheme 5.55). 

A comprehensive review (260 refs.) on the synthesis of carbohydrates from noncarbohydrate sources covers the use of benzene-derived diols and products of Sharpless asymmetric oxidation as starting materials, Dodoni s thiazole and Vogel s naked sugar approaches, as well as the application of enzyme-catalysed aldol condensations. The preparation of monosaccharides by enzyme-catalysed aldol condensations is also discussed in a review on recent advances in the chemoenzymic synthesis of carbohydrates and carbohydrate mimetics, in parts of reviews on the formation of carbon-carbon bonds by enzymic asymmetric synthesis and on carbohydrate-mediated biochemical recognition processes as potential targets for drug development, as well as in connection with the introduction of three Aldol Reaction Kits that provide dihydroxyacetone phosphate-dependent aldolases (27 refs.). A further review deals with the synthesis of carbohydrates by application of the nitrile oxide 1,3-dipolar cycloaddition (13 refs.). ... 

Other than the L-DOPA, there have been two other significant processes developed for industrial applications. The first of these uses a Sharpless asymmetric epoxidation, one of the most widely applied asymmetric transition metal catalysed transformations, to convert allyl alcohol (41) into (5)-glycidol (43), a valuable chiral building block, developed by ARCO Chemical Company (Scheme 4.12) [29]. Most of the successful applications of transition metal mediated asymmetric... 

Many other compounds have potential as artificial sweeteners. For example, l sugars are also sweet, and they presumably would provide either zero or very few calories because our enzymes have evolved to selectively metabolize their enantiomers instead, the d sugars. Although sources of L sugars are rare in nature, all eight L-hexoses have been synthesized by S. Masamune and K. B. Sharpless using the Sharpless asymmetric epoxidation (Sections 11.13 and 22.11) and other enantioselective synthetic methods. 

In 2009, Donohoe et al. reported a total synthesis of the natural products (-l-)-ds-sylvaticin 19 and (-l-)-sylvaticin 20 using a Sharpless asymmetric dihydroxylation of diene 15 with an osmium catalyst as key step to give the diol 16. This was followed by an oxidative cychzation to yield the functionalized tetrahydrofuran (THF) 18 stereoselectively through the cychc intermediate 17 (Scheme 9.4) [10]. 

A synthesis of cytovaricin includes a synthesis of D-cymarose (using a Sharpless asymmetric oxidation procedure on a non-carbo-... 

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